The Multiple Faces of Systemic Lupus Erythematosus: Pearls and Pitfalls for Diagnosis

Systemic lupus erythematosus is the prototype multisystem autoimmune disorder characterised by a broad spectrum of organ involvement and a multitude of laboratory abnormalities. Clinical heterogeneity, unpredictable course and lack of pathognomonic clinical and serological features pose a considerable challenge in the diagnosis of SLE. The latter remains largely clinical, typically accompanied however by features of serologic autoimmunity, which are characteristic for the disease. Despite significant improvements in treatment strategies, an early diagnosis often continues to be an unmet need, as the median reported delay from symptom onset to SLE diagnosis is approximately 2 years. Classification criteria are usually used to support the diagnosis, yet with significant caveats. In this article, we provide an updated review of the clinical presentation of lupus and give clues for an accurate diagnosis.


INTRODUCTION
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a broad spectrum of clinical manifestations and accompanying laboratory abnormalities. 1,2][20][21][22][23] Although a universally accepted definition of what constitutes "early" diagnosis is lacking, and a window of opportunity for timely treatment has not been clearly defined, some studies suggest that patients diagnosed within 6 months from symptom onset experience lower rates of flares, hospitalisations, healthcare utilisation costs, and disease-related damage.The various sets of classification criteria of SLE reflect the multifaceted nature of the disease and they have been primarily developed to ensure the inclusion of homogeneous groups of patients in clinical and epidemiological studies. 2628][29] Following the first classification criteria from the American College of Rheumatology (ACR), 30 the SLICC criteria, published in 2012, aimed for earlier diagnosis and higher sensitivity, by necessitating the patient to satisfy ≥4criteria (at least one clinical and one immunologic), or to have biopsy-proven lupus nephritis in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA antibodies. 31][34][35][36][37][38][39] The most recent set of classification criteria have been published in 2019 following a combined effort from the European League Against Rheumatism (EULAR)/ACR, and requiring a positive ANA test at least once as entry criterion, combined with at least 10 additional points derived from weighted criteria, grouped in 7 clinical and 3 immunologic domains. 40Data from the validation cohort suggested that the EULAR/ACR-2019 criteria achieved a higher and similar sensitivity as compared with ACR 1997 (96.1% vs 82.8%) and SLICC 2012 (96.1% vs 96.7%), respectively. 40Accordingly, the specificity was similar to ACR 1997 criteria (93.4% vs 93.4%), but higher than SLICC 2012 (93.4% vs 83.7%). 402][43][44][45] The performance of existing sets of SLE classification criteria in several real-life patient cohorts is shown in Table 1.
A diagnosis is often most challenging in the early stages of the disease, when the latter may manifest only a few or even a single clinical manifestation (organ-dominant lupus). 7,41,51In such settings, application of existing sets

TITLE SLE DIAGNOSIS: PEARLS AND PITFALLS
of classification criteria may assist diagnosis; in fact, the combination of all three sets ensures the highest sensitivity. 25,27,41Importantly, a recent retrospective study showed that different sets of criteria still fail to classify a significant proportion of cases at the time of diagnosis by an expert, and thus some patients with potentially high disease burden may be "missed". 41This study proposed that modifications of classification criteria, such as the use of an alternative entry criterion in ANA-negative patients or the classification of patients with fewer criteria from multiple domains, may enhance their diagnostic accuracy, enabling an earlier diagnosis and timely treatment of more patients. 41ecently, Adamichou et al. introduced a clinically applicable model to assist SLE diagnosis, by the use of machine learning. 52The SLE Risk Probability Index (SLERPI) consists of 14 variably weighted clinical and serological SLE features, that can produce individualised risk probabilities for clinical SLE against competing rheumatologic diseases (i.e., "definite", "likely/probable", "possible", "unlikely"), alike clinical diagnostic reasoning.In the binary model, a threshold >7 can be used as a dichotomous algorithm (i.e., SLE or not) with high accuracy (94.2%) for SLE diagnosis, including early and severe disease. 52By operating the full probabilistic model, the algorithm can be used to exclude SLE (risk probability <14%), confirm SLE (risk probability >86%), or suggest identification and monitoring of patients with intermediate probabilities (15-85%). 52Recent studies on SLERPI performance showed a similar or higher sensitivity [98.5% (95% CI; 96.7%-99.4%)]5][56] Further research in cohorts with larger samples and diverse ethnic/racial characteristics, is needed to further establish the clinical utility and diagnostic value of this tool.

CLINICAL PRESENTATION OF SLE How does lupus present?
A typical pattern of presenting clinical picture for lupus does not exist.Moreover, what makes the diagnosis often challenging, is the fact that the diverse array of manifestations often do not appear simultaneously but rather accumulate gradually over the disease course, occasionally with a time interval of several months or even years between them. 16,24,32Additionally, a considerable proportion of patients present with non-specific manifestations, such as arthritis, fever or fatigue, or with rare and atypical features, such as unusual rashes, neuropsychiatric manifestations, or abdominal vasculitis, among others.A small but challenging group of patients might present with single-organ involvement, the so called 'organ-dominant lupus'. 4,25Sex, age and ethnicity may also influence the expression of SLE, as people of white race tend to develop milder phenotypes compared to Blacks or Asians. 4,12,16,57ucocutaneous lesions and musculoskeletal involvement are almost universal in SLE, occurring in about 90% of SLE patients.Arthralgias and true synovitis are very common manifestations, with the majority of patients manifesting a symmetric non-erosive polyarthritis, usually early in the disease course. 4,32,57upus nephritis (LN) represents one of the most characteristic manifestations and usually, although not exclusively, occurs early in the disease course.][59][60][61][62] Hematologic involvement is also a frequent manifestation and can be a presenting manifestation of SLE.Its clinical presentation is highly variable, including the possible involvement of all three blood cell lines, while occasionally can be associated with severe lupus disease. 32,57,63][66][67] Neuropsychiatric lupus (NPSLE) prevalence varies widely among different cohorts, owing to differences in definition and attribution to the disease per se.][70][71][72] Importantly, non-infectious fever, recently included as a criterion in the 2019 EULAR/ACR criteria, with data from different early SLE cohorts, suggest the importance of this manifestation as an early feature, despite its obviously low specificity. 8,10

MULTISYSTEM VERSUS ORGAN-DOMINANT DISEASE
A minority of SLE patients may present with organ-dominant disease, often with a severe clinical manifestation. 25he diagnosis of organ-dominant disease is challenging, because these patients typically do not fulfil classification criteria; in these circumstances, judgment of a physician experienced in SLE may result in a diagnosis of 'possible SLE', only after rigorous exclusion of alternative causes for the patient's symptoms.In such clinical scenarios, the diagnosis can be substantiated in patients displaying manifestations with a high specificity for SLE (e.g., malar rash, positivity for SLE-specific autoantibodies, such as anti-dsDNA or anti-Smith), or when there is histologic suspicion or confirmation of lupus, particularly in cases of nephritis and cutaneous lupus.In patients not falling into one of these categories, the diagnosis of SLE may be delayed until additional clinical or serological features accumulate, potentially affecting the long-term prognosis.For patients presenting with mild-moderate single-organ symptoms, a strategy of 'watchful waiting' or a therapeutic trial with low to moderate dose of glucocorticoids might be beneficial.By contrast, prompt interventions are needed for patients presenting with severe or life-threatening manifestations.In such situations, an aggressive work-up is warranted to rule out other life-threatening conditions, particularly those that can be exacerbated by immunosuppressive treatments like infections.Following this, with a possible diagnosis of SLE, immunosuppressive treatment is justified, under the supervision of an experienced SLE physician and multidisciplinary evaluation.Revisiting the accuracy of the diagnosis after a period of time in doubtful cases is of utmost importance. 73ontrary to organ-dominant presentation, diagnosing SLE in patients with multisystem involvement is generally considered as more straightforward, because these individuals usually have a more familiar clinical picture for physicians with less experience in the disease. 41onetheless, it is still important to consider various conditions that mimic SLE in the differential diagnosis, especially when specific features are absent.In cases with more benign clinical presentations, an optimal evaluation should rule out other connective tissue diseases and chronic infections, in the presence of suggestive symptoms.In patients with severe multi-system SLE requiring hospitalisation, it's essential to consider viral infections, sepsis and full-blown vasculitis as potential alternative diagnoses that should be part of the corresponding diagnostic work-up.In this regard, the diagnosis of SLE always demands a holistic assessment that should be adapted to each individual case based on disease severity and available clinical and laboratory findings.

SEX-AGE DIFFERENCES AND THE ROLE OF ETHNICITY
The incidence of childhood-onset SLE (cSLE, diagnosis in patients < 16 years old) among all SLE cases may account for up to 20% in different cohorts, 74 while a similar incidence at 10-20% has been reported for SLE patients with late-onset disease (i.e.diagnosis after 50 years). 75][77] Traditionally, cSLE is considered a more severe form of lupus characterised by high disease activity, early accumulation of damage and increased need for potent immunosuppressive therapy. 74In a large cohort from the UK including patients with different ethnic backgrounds, cSLE was associated with a higher frequency of lupus nephritis, mucocutaneous manifestations, thrombocytopenia, haemolytic anaemia, seropositivity for SLEspecific antibodies, and with increased mortality rates, while adult-onset SLE patients were more like to exhibit arthritis and leukopenia. 78On the other hand, patients with late-onset SLE exhibit more frequently serositis and pulmonary involvement. 75,79Two recent studies comparing cSLE with late-onset disease showed that cSLE tend to manifest more frequently lupus nephritis, acute cutaneous lupus, alopecia, oral ulcers, and fever, while late-onset-SLE was linked to increased incidence of pleuritis and pericarditis. 58,80he characteristic 9-10:1 female-to-male ratio in SLE seems to diminish with increasing age at diagnosis, reaching as low as 2.6:1 for patients with late-onset disease and indicating that male patients tend to develop SLE at an older age. 75In a recent cohort study, male SLE patients had a higher mean age at disease onset and frequency of late-onset SLE. 81Numerous studies have sought to discern disparities between male and female SLE phenotypes, yielding conflicting findings.Nevertheless, a common trend in these studies suggests that male patients are more inclined to experience serositis, thrombosis, and late-onset disease. 822][83][84] Male SLE patients accumulate irreversible damage earlier in the disease course and have significantly higher SLICC damage index scores within the 5 first years of the disease, suggesting a more aggressive phenotype. 85acial and ethnic background is an additional major determinant of the lupus phenotype.Collectively, most studies suggest a more severe disease in black, Hispanic, and Asian patients. 86Multi-ethnic cohort studies demonstrated that white patients exhibited the lowest prevalence of LN, while Asians are less likely to manifest neuropsychiatric events. 59Musculoskeletal and skin manifestations are commonly observed among white individuals, while chronic cutaneous lupus is more frequent among black SLE patients. 58,87Immune-mediated cytopenias are typical manifestations among patients of Asian origin, while serositis appears to be more prevalent in Hispanics. 86,88With respect to antibodies, Black and Asian individuals are more commonly positive for anti-Smith and anti-dsDNA, while antiphospholipid antibodies are more often positive in white SLE patients compared to other ethnicities. 86ased on all of the above, it becomes evident that physicians of multiple disciplines need to be well-informed about the varying SLE presenting pictures based on a patient's sex, age and racial/ethnic background, in order to be able to tailor the diagnostic work-up for each individual patient.

DIAGNOSIS OF LUPUS IN THE HOSPITAL SETTING
Although the majority of lupus patients are usually diagnosed in an outpatient setting, SLE can occasionally first present with severe or critical disease necessitating hospitalisation. 56,58Previous studies have reported significant variations in rates of hospitalisation and reasons of admission, mainly reflecting underlying socioeconomic and ethnic differences.Approximately 10-20% of SLE patients are hospitalised annually, the most common causes of admission being active disease (11%-80.8%)][94][95][96][97] The clinical presentation of lupus flare in hospital setting varies among different studies and usually reflect severe forms of the disease.Lupus nephritis and haematological disorders are identified as the most frequent flare manifestations in most studies, accounting for 17.2%-63.4%3][94][95][96][97] We recently studied the clinical phenotypes of SLE patients diagnosed during hospitalisation and found that neuropsychiatric syndromes were the most common ones leading to admission, comprising 21% of patients (a generally higher proportion compared with previous literature, 1.6%-24.8%). 5695][96][97]100

PRECLINICAL SLE, INCOMPLETE SLE AND UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE
The period preceding a formal diagnosis of SLE has been referred to as "preclinical lupus", "lupus-like disease" or "incomplete lupus" (ILE).Although there are no universally accepted definitions for these entities, in older literature ILE typically pertained to patients who had one or more, but fewer than four, ACR SLE classification criteria. 101Undifferentiated connective tissue disease (UCTD) is a broader term used for individuals who exhibit symptoms suggestive of a CTD but do not meet specific classification criteria for any. 102Among patients with UCTD, a small proportion (10-20%) will eventually develop SLE. 103To date, no single biomarker has been shown to predict the progression of these patients to definite SLE, thus, only close follow-up will promptly capture those individuals who transition to SLE.5][106][107] Importantly, ILE patients who transition to SLE during follow-up tend to exhibit a more benign disease course, characterised by a lower incidence of major organ involvement. 103] Importantly, patients with either ILE or UCTD tend to progress to SLE within the first years following diagnosis, signifying the need for more tight monitoring during this early period. 110n contrast to incomplete/undifferentiated forms of lupus, preclinical SLE typically refers to individuals with serological evidence of autoimmunity (e.g., positivity for ANA and/or other autoantibodies), without any evident clinical symptoms.Several studies have been conducted to identify risk factors associated with the transition from the pre-clinical stage to definitive SLE, with the primary objective to minimise diagnostic delay.Approximately 90% of patients with SLE develop autoantibodies prior to diagnosis. 111Notably, non-specific antibodies including ANA, anti-phospholipid, anti-Ro, and anti-La, were detected at an earlier pre-clinical stage compared to SLE-specific antibodies, such as anti-Sm and anti-dsDNA antibodies. 111A Swedish SLE cohort study showed that 63% of SLE patients develop ANA approximately 5 years prior to the diagnosis, whereas anti-Sm antibodies become detectable closer to the time of diagnosis. 112Nevertheless, only a minority of SLE patients carry SLE-specific antibodies during the pre-clinical phase.Furthermore, non-specific antibodies, particularly ANA, are prevalent in a range of autoimmune disorders and can also be found in individuals without autoimmune conditions, rendering them unsuitable for diagnostic purposes.Results from the same Swedish cohort indicated that increased levels of IP-10 (interferon gamma induced protein 10) and interferon-a (IFN-a) are evident in SLE patients at pre-clinical stage. 113Indeed, recent evidence demonstrate that IFN-α might potentially serve as a surrogate marker for the transition from the pre-clinical stage to established SLE, and validation studies are currently in progress.In this regard, a higher IFN score along with family history could help to identify ANA-positive individuals who will progress to definitive connective tissue disease, including SLE, although IFN upregulation (albeit lower) was evident even in ANA-positive individuals who did not ultimately progress to SLE. 114 Ongoing research in the field of preclinical disease is of utmost importance for uncovering diagnostic biomarkers SLE DIAGNOSIS: PEARLS AND PITFALLS

Table 1 .
Performance of different SLE classification criteria in real-life settings.
SLE: Systemic Lupus Erythematosus; ACR: American College of Rheumatology; SLICC: Systemic Lupus International Collaborating Clinics; EULAR: European Alliance of Associations for Rheumatology; ACR: American College of Rheumatology; N/A: not applicable.